EP0815091B1 - Composes de polyazacycloalcane - Google Patents

Composes de polyazacycloalcane Download PDF

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EP0815091B1
EP0815091B1 EP96904204A EP96904204A EP0815091B1 EP 0815091 B1 EP0815091 B1 EP 0815091B1 EP 96904204 A EP96904204 A EP 96904204A EP 96904204 A EP96904204 A EP 96904204A EP 0815091 B1 EP0815091 B1 EP 0815091B1
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phenyl
optionally substituted
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EP0815091A1 (fr
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Lisa Schultze
Alan Ray Bulls
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GE Healthcare AS
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Nycomed Imaging AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings

Definitions

  • This invention relates to polyazacycloalkane compounds, to processes for their preparation and to their use in the production of macrocyclic chelating agents.
  • chelating agents In the field of diagnostic medical imaging, complexes of paramagnetic metal ions are widely used as contrast agents.
  • the lanthanide metal ions, especially Gd(III) and Dy(III) are among the most effective MR contrast enhancers and to ensure appropriate biodistribution and post-contrast bioelimination, they are administered in chelate complexes which have very high stability constants.
  • some of the chelating agents used have a linear polyamine structure (eg. DTPA as in Schering's GdDTPA product Magnevist and DTPA-BMA as in Nycomed Imaging's GdDTPA-BMA product Omniscan)
  • others have a macrocyclic polyamine structure, eg. DOTA as in Guerbet's GdDOTA product Dotarem and HP-D03A as in Squibb's GdHP-D03A product ProHance.
  • the 1,4,7,10-tetraazacyclododecane (cyclen) polyamine skeleton of DOTA and HP-D03A forms the basis for a range of particularly stable lanthanide-chelating macrocyclic chelants in which three or four of the ring nitrogens carry a pendant, ionizable metal coordinating group, eg. a carboxylic or phosphonic acid group. Since the lanthanide ions of interest are generally in the III state, cyclen-based chelants carrying three such acid groups offer the opportunity to produce charge-neutral or non-ionic chelate complexes. This is of importance since various side effects of contrast agent compositions are associated with hypertonicity and non-ionic contrast agents have a lower contribution to the overall osmolality of the composition.
  • Cyclen is a key intermediate in the preparation of such macrocyclic chelating agents, with the ring nitrogens being appropriately substituted after macrocyclic ring formation has occurred.
  • DOTA 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid
  • EP-A-0374929 describes a process for selectively preparing mono-N-alkylated polyazamacrocycles by varying the solvent, the temperature, the electrophile and the molar ratio between the macrocycle and the electrophile, another is to start from a mono-substituted cyclen produced for example by condensing a triamine with a monoamine, with one of the two amine reagents carrying the substituent group (eg.
  • WO-A-89/01476 describes tetrazamacrocycles in which one of the ring carbon atoms is substituted by a functional group (optionally through a linker group) and the nitrogen atoms are optionally substituted by a variety of different groups.
  • the present invention is based on the finding that, for the production of chelating agents comprising triacid substituted cyclen, a particularly straightforward and flexible route is offered via the N,N',N"-tribenzylcyclens, compounds which are themselves novel.
  • the invention provides tribenzylcyclen compounds of formula I (where Ph is phenyl, R is hydrogen, or a C 1-12 alkyl group optionally substituted by hydroxy, alkoxy or aryl groups or R is an amphiphilic aralkyl group comprising a N, S, O or P interrupted C 2-25 alkylene chain, e.g.
  • a polyalkylene oxide chain or R provides a bridge to a second tribenzylcyclen group, but with the proviso that R is other than benzyl;
  • X is CHR 1 , or where R is hydrogen two X groups may each represent CO groups; and
  • R 1 is hydrogen, a C 1-6 alkyl group optionally substituted by hydroxy, alkoxy or carboxy groups or an aralkyl group having 1 to 6 carbons in the alkyl moiety and optionally substituted in the aryl moiety by alkyl, alkoxy, hydroxy or isothiocyanate groups).
  • any alkyl or alkylene moiety unless otherwise specified conveniently contains 1 to 12, preferably 1 to 6, carbons and any aryl group is a phenyl group.
  • An amphiphilic chain R group is a group L-Ar(-AH) n where each L is an C 2-25 -alkylene linker wherein at least one CH 2 moiety is replaced by X 1 or a group X 1 (CH 2 CH 2 X 1 ) u (where u is a positive integer) such as X 1 CH 2 CH 2 X 1 , X 1 CH 2 CH 2 X 1 CH 2 CH 2 X 1 , X 1 CH 2 CH 2 X 1 CH 2 CH 2 X 1 CH 2 CH 2 X 1 , etc), but with the provisos that the terminus of L adjacent the cyclen ring is CH 2 and that the terminus of L adjacent Ar is X 1 or a CH 2 group adjacent or separated by one CH 2 from a group X 1 (thus for example the L-Ar linkage may be L 1 -X 1 -Ar, L 1 -CH 2 -Ar, L 1 -X 1 CH 2 -Ar or L 1 -X 1 CH 2
  • each X 1 is O, S, NR 2 or PR 2 ; each R 2 is hydrogen, alkyl or phenyl and n is a positive integer for example 1, 2 or 3.
  • carbonyl X groups are present, eg. as in the case where the compound is produced by a cyclization involving amines having N-attached LvCOCH 2 or LvCH 2 CO groups (where Lv is a leaving group such as a halogen atom), the compound can readily be reduced to the analogous compound of formula I wherein all X groups are CH 2 .
  • the compounds of formula I wherein R is hydrogen may readily be prepared by diamine:diamine or monoamine: triamine cyclizations. If any carbonyl groups are present these can be reduced and the tribenzyl cyclen product can then be reacted to introduce a non-hydrogen R group. Debenzylation and carboxymethylation or phosphonomethylation then yield an R-DO3A compound (or the phosphonic acid equivalent) which can if desired be further converted to desired DO3A compounds by deprotection or removal of the R group followed if desired by substitution of the free ring nitrogen with a desired end group.
  • the invention provides the use of compounds of formula I for the preparation of DO3A, N-substituted-1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetic acids, and the phosphonic acid analogs.
  • the invention provides a process for the preparation of a compound of formula I, said process comprising at least one of the following steps:
  • the reagents of formulae II and VI can be prepared by reaction of ethylenediamine or diethylenetriamine with a benzylating agent, eg. a compound PhCH 2 Lv or with benzaldehyde followed by catalytic reduction of the imino product.
  • a benzylating agent eg. a compound PhCH 2 Lv or with benzaldehyde followed by catalytic reduction of the imino product.
  • the reagent of formula III may be prepared by benzylating ethylenediamine, eg. as described for the compounds of formulae I and VI, and acylating the benzylamine product, eg. by reaction with chloroacetylbromide or bromoacetylchloride or other haloacetylhalides or comparable doubly-activated acetic acid reagents.
  • the iminodiacetic acid derivatives of formula VII can be prepared by conventional carboxylic acid activation procedures.
  • steps (c) and (d) may be performed by conventional means as can the deprotection stages which may be required.
  • Debenzylation will preferably be effected by catalytic hydrogenation, eg. at a hydrogen pressure of 10 to 1000 psi, preferably 30-200 psi, a temperature of 0 to 200°C, preferably 25 to 120°C, and over a conventional hydrogeneration catalyst such as palladium/charcoal or platinum/C. Debenzylation is described by Rylander in “Catalytic hydrogeneration over platinum metals” Academic Press, 1967, pages 449 to 468.
  • Loading of acid groups, eg. carboxymethyl or phosphonomethyl groups, onto the debenzylated cyclen can again be effected using conventional procedures, eg. reaction with bromoacetic acid, t-butyl-bromoacetate or by reaction with formaldehyde and phosphorous acid followed where necessary by removal of any protecting groups and amidation if desired.
  • the invention provides improved routes for high yield production of cyclen tri-substituted by acid groups and optionally mono-substituted by a desired further group, eg. DO3A HP-DO3A, or other hydroxyalkyl-DO3As, as well as DO3A-DO3A dimers.
  • a desired further group eg. DO3A HP-DO3A, or other hydroxyalkyl-DO3As, as well as DO3A-DO3A dimers.
  • the products will generally be subjected to N-alkylation in order to produce the desired chelating agents.
  • the N-alkylation step to introduce desired alkyl or substituted alkyl groups onto the macrocyclic skeleton can be performed using conventional alkylation techniques, for example involving reaction with an alkylhalide R 2 -Hal (where Hal is a halogen atom such as chlorine or bromine and R 2 is an alkyl group optionally substituted, for example by hydroxy or alkoxy groups or by chelant moieties, such as carboxyamide groups or carboxyl or phosphonic acid groups (optionally protected by ester groups)).
  • R 2 -Hal where Hal is a halogen atom such as chlorine or bromine and R 2 is an alkyl group optionally substituted, for example by hydroxy or alkoxy groups or by chelant moieties, such as carboxyamide groups or carboxyl or phosphonic acid groups (optionally protected by ester groups)
  • the alkyl moiety in R 2 will conveniently contain 1 to 12 carbon atoms and any chelant moiety will preferably be on the alpha or beta carbon.
  • the macrocyclic chelating agents can be used in metallated or unmetallated forms. In the latter case they may for example be used as therapeutic agents, eg in the treatment of cancer.
  • Metallation of the macrocyclic chelating agent may be effected by conventional methods, for example as described in the patent literature relating to MR contrast agents (see for example EP-A-71564, EP-A-130934, EP-A-165728, EP-A-258616, WO-A-86/06605, etc.).
  • metal ions to be complexed will depend upon the intended end use for the chelate complex. Especially preferred are ions of metals of atomic numbers 22 to 32, 42 to 44, 49 and 57 to 83, in particular Gd.
  • the chelated metal species is conveniently a paramagnetic ion of a transition metal or a lanthanide, preferably having an atomic number of 21 to 29, 42, 44 or 57 to 71.
  • Complexes of Eu, Gd, Dy, Ho, Cr, Mn and Fe are especially preferred and Gd 3+ , Mn 2+ and Dy 3+ are particularly preferred ions.
  • the paramagnetic metal species is conveniently non-radioactive as radioactivity is a characteristic which is neither required nor desirable.
  • the metal is preferably a heavy metal such as a non-radioactive metal with an atomic number greater than 37, preferably greater than 50, for example Dy 3+ .
  • the chelated metal species must of course be radioactive and any conventional complexable radioactive isotope, such as 99m Tc or 111 In for example may be used.
  • the chelated metal may for example be 153 Sm, 67 Cu or 90 Y.
  • EXAMPLE 1 N-benzylethylenediamine 1 and N,N'-dibenzylethylenediamine 2 .
  • EXAMPLE 2 N,N'-Bis(chloroacetyl)-N-benzylethylenediamine 3 .
  • a 2-L, 3-neck, round bottom flask equipped with an overhead stirrer, an addition funnel and a thermometer was charged with 69.86g (0.444mol) of bromoacetyl chloride, 750mL of CH 2 Cl 2 , and 62g (0.449mol) of K 2 CO 3 .
  • the mixture was chilled to between 5 and 10°C before slowly adding 28.99g (0.193mol) of 1 in 250mL of CH 2 Cl 2 while maintaining the temperature at ca.10°C.
  • the reaction mixture was stirred for 1 ⁇ 2 hour at 10 to 15°C. Water (250mL) was then carefully added to the chilled mixture (5 to 10°C). The organic layer was separated.
  • EXAMPLE 4 1,4,7-tribenzyl-1,4,7,10-tetraaza-2,9-dioxocyclododecane 5 .
  • EXAMPLE 6 1,14-dibromo-2,13-dioxo-3,12-diaza-6,9-dioxa-tetradecane 7 .
  • EXAMPLE 7 1,14-bis(4,7,10-tribenzyl-1,4,7,10-tetraazacyclododecyl)-2,13-dioxo-3,12-diaza-6,9-dioxatetradecane 8 .
  • EXAMPLE 8 1,14-bis-(1,4,7,10-tetraazacyclododecyl)-2,13-dioxo-3,12-diaza-6,9-dioxatetradecane 9 .
  • EXAMPLE 9 1,14-bis-(4,7,10-tris(carboxymethyl-benzyl ester)-1,4,7,10-tetraazacyclododecyl)-2,13-dioxo-3,12-diaza-6,9-dioxatetradecane 10 .
  • EXAMPLE 10 1,14-bis-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl)-2,13-dioxo-3,12-diaza-6,9-dioxatetradecane 11 .
  • EXAMPLE 11 [1,14-bis-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl)-2,13-dioxo-3,12-diaza-6,9-dioxatetradecane] Gd(III) chelate 12 .
  • EXAMPLE 13 1,4,7-tris(carboxymethyl-tert-butyl ester)-1,4,7,10-tetraazacyclododecane 14 .
  • EXAMPLE 14 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane 15 .
  • EXAMPLE 15 1,4,7-tris(carboxymethyl)-10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane 16 .
  • EXAMPLE 16 [1,4,7-tris(carboxymethyl)-10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane] gadolinium 17 .
  • EXAMPLE 17 [1,4,7-tris(carboxymethyl)-10-(10-(3,5-dicarboxyphenyl)-decyl) -1,4,7,10-tetraazacyclododecane] 18 .
  • a round bottom flask equipped with a reflux condenser is charged with 0.2mols of tribenzylcylen, 0.2mols of 10-(3,5-dicarboxyphenyl)-1-bromodecane, 1 litre of DMF and 0.2mols of tetramethylguanidine (TMG).
  • TMG tetramethylguanidine
  • the reaction mixture is stirred for ca. 12-16 hours at 60-65°C.
  • the bulk of the DMF is removed under vacuum. Work-up from CH 2 Cl 2 /H 2 O affords the alkylated tribenzylcyclen intermediate.
  • the alkylated tribenzylcyclen intermediate is debenzylated as follows: A 100mL Autoclave pressure reactor is charged with ca. 10mmol of substrate, 50mL of ethanol and 3g of 10% Pd/C. The reactor is pressurized to 100-200psig with hydrogen for 3 hours at 80°C. The mixture is filtered to remove the catalyst and the filtrate is evaporated to give 1-[10-(3,5-dicarboxyphenyl) -decyl]-1,4,7,10-tetraazacyclododecane.
  • EXAMPLE 18 [1,4,7-tris(carboxymethyl)-10-(2-(1,3,4-trihydroxybutyl)]-1,4,7,10-tetraazacyclododecane] 19 .
  • a round bottom flask equipped with a reflux condenser is charged with 1 liter of acetonitrile, 0.2mols of tribenzylcyclen and 0.2 moles of 1,4-dihydroxy-2-butene oxide.
  • the reaction mixture is stirred for ca. 12-16 hours at 60-65°C.
  • the bulk of the acetonitrile is removed under vacuum. Work-up from CH 2 Cl 2 /H 2 O affords the trihydroxybutyl tribenzylcyclen intermediate.
  • the trihydroxybutyl tribenzylcyclen intermediate is debenzylatyed as follows: A 100mL Autoclave pressure reactor is charged with ca.10mmol of substrate, 50mL of ethanol and 3g of 10% Pd/C. The reactor-is pressurized to 100-200psig with hydrogen for 3 hours at 80°C. The mixture is filtered to remove the catalyst and the filtrate is evaporated to give 1-[2-(1,3,4-trihydroxybutyl)]-1,4,7,10-tetraazacyclododecane.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)

Claims (3)

  1. Tribenzyl-1,4,7,10-tétraazacyclododécanes de formule I
    Figure 00340001
    (dans laquelle Ph représente un groupe phényle).
    R, qui ne représente pas un groupe benzyle, représente un atome d'hydrogène ou un groupe alkyle en C1-12 éventuellement substitué par un groupe hydroxy, un groupe alcoxy ou un groupe phényle,
    ou R représente un groupe amphiphile L-Ar(-AH)n (où chaque L représente un groupe de liaison alkylène en C2-25 dans lequel au moins un fragment CH2 est remplacé par X1 ou un groupe X1(CH2CH2X1)u (où u représente un nombre entier positif) mais à condition que le groupe terminal de L adjacent au cycle 1,4,7,10-tétraazacyclododécane soit CH2 et que le groupe terminal de L adjacent à Ar soit X1 ou un groupe CH2 adjacent ou séparé par un groupe CH2 d'un groupe X1 ;
    chaque Ar représente un cycle phényle éventuellement substitué par un autre cycle phényle ou condensé avec un autre cycle phényle ;
    chaque AH représente un oxyacide ou un sel de celui-ci ;
    chaque X1 représente O, S, NR2 ou PR2 ;
    chaque R2 représente un atome d'hydrogène, un groupe alkyle ou phényle ;
    et n représente un nombre entier positif),
    ou R forme un pont vers un second groupe tribenzyl-1,4,7,10-tétraazacyclododécane ;
    X représente CHR1, ou lorsque R représente un atome d'hydrogène, deux groupes X peuvent chacun représenter des groupes CO ; et R1 représente un atome d'hydrogène, un groupe alkyle en C1-6 éventuellement substitué par des groupes hydroxy, alcoxy ou carboxy ou un groupe aralkyle comportant de 1 à 6 atomes de carbone dans sa partie alkyle et dans lequel la partie aryle est un groupe phényle éventuellement substitué par des groupes alkyle, alcoxy, hydroxy ou isothiocyanate.
  2. Composé selon la revendication 1 dans lequel tous les groupes X sont des groupes CH2.
  3. Procédé de préparation d'un composé de formule I tel que défini dans la revendication 1, ledit procédé comprenant au moins une des étapes suivantes :
    (a) faire réagir une diamine de formule II PhCH2NHCHR1CHR1NHCH2Ph (dans laquelle R1 et Ph sont tels que définis dans la revendication 1) avec une diamine de formule III YN (CH2Ph)CHR1CHR1NHY (dans laquelle Y représente CH2COLv ou COCH2Lv et Lv représente un groupe partant) pour obtenir un composé de formule IV ou V
    Figure 00350001
    Figure 00360001
    (b) faire réagir une triamine de formule VI Z1NHCHR1CHR1N (Z2) CHR1CHR1NHZ3 avec une monoamine de formule VII Z4N(CHR1COLv)2 pour obtenir un composé de formule VIII
    Figure 00360002
    (dans laquelle R1 est tel que défini dans la revendication 1, un des Z1, Z2, Z3 et Z4 représente un atome d'hydrogène et les autres représentent des groupes benzyle) ;
    (c) réduire un composé de formule IV, V ou VIII pour obtenir un composé de formule IX
    Figure 00370001
    (dans laquelle R1 et Ph sont tels que définis dans la revendication 1) ;
    (d) faire réagir un composé de formule IX avec un composé de formule X Lv-R1 (dans laquelle Lv représente un groupe partant et R1 (qui ne représente pas un groupe benzyle) représente un groupe alkyle en C1-12 éventuellement substitué par un groupe hydroxy, un groupe alcoxy ou un groupe phényle éventuellement substitué, ou R1 représente un groupe amphiphile L-Ar(-AH)n (où chaque L représente un groupe de liaison alkylène en C2-25 dans lequel au moins un fragment CH2 est remplacé par X1 ou un groupe X1(CH2CH2X1)u (où u représente un nombre entier positif) mais à condition que le groupe terminal de L adjacent au cycle 1,4,7,10-tétraazacyclododécane soit CH2 et que le groupe terminal de L adjacent à Ar soit X1 ou un groupe CH2 adjacent ou séparé par un groupe CH2 d'un groupe X1 ;
    chaque Ar représente un cycle phényle éventuellement substitué par un autre cycle phényle ou condensé avec un autre cycle phényle ;
    chaque AH représente un oxyacide ou un sel de celui-ci ;
    chaque X1 représente O, S, NR2 ou PR2 ;
    chaque R2 représente un atome d'hydrogène, un groupe alkyle ou phényle ;
    et n représente un nombre entier positif),
    ou R1 forme un pont vers un second groupe tribenzyl-1,4,7,10-tétraazacyclododécane ;
    ou dans laquelle Lv-R1 est un composé cyclique ou insaturé pouvant subir une substitution nucléophile par un atome d'azote d'une amine pour donner un groupe R1 attaché à N) ;
    (e) faire réagir une monoamine de formule XI LvCHR1CHR1NR2CHR1CHR1Lv (dans laquelle R2 représente un groupe alkyle en C1-12 éventuellement substitué par un groupe hydroxy, un groupe alcoxy ou un groupe phényle éventuellement substitué, ou R2 représente un groupe amphiphile L-Ar(-AH)n (où chaque L représente un groupe de liaison alkylène en C2-25 dans lequel au moins un fragment CH2 est remplacé par X1 ou un groupe X1(CH2CH2X1)u (où u représente un nombre entier positif) mais à condition que le groupe terminal de L adjacent au cycle 1,4,7,10-tétraazacyclododécane soit CH2 et que le groupe terminal de L adjacent à Ar soit X1 ou un groupe CH2 adjacent ou séparé par un groupe CH2 d'un groupe X1 ;
    chaque Ar représente un cycle phényle éventuellement substitué par un autre cycle phényle ou condensé avec un autre cycle phényle ;
    chaque AH représente un oxyacide ou un sel de celui-ci ;
    chaque X1 représente O, S, NR2 ou PR2 ;
    chaque R2 représente un atome d'hydrogène, un groupe alkyle ou phényle ;
    et n représente un nombre entier positif),
    ou un groupe protecteur de l'atome d'azote) avec une triamine de formule VI dans laquelle Z1, Z2 et Z3 représentent des groupes benzyle et, si nécessaire, déprotéger l'atome d'azote substitué par R2 dans le tribenzyl-1,4,7,10-tétraazacyclododécane résultant.
EP96904204A 1995-03-10 1996-03-01 Composes de polyazacycloalcane Expired - Lifetime EP0815091B1 (fr)

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GB9504910 1995-03-10
GBGB9504910.2A GB9504910D0 (en) 1995-03-10 1995-03-10 Compounds
PCT/GB1996/000464 WO1996028433A1 (fr) 1995-03-10 1996-03-01 Composes de polyazacycloalcane
US08/790,855 US5705637A (en) 1995-03-10 1997-02-03 Polyazacycloalkane compounds

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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4340809C2 (de) * 1993-11-24 2000-08-03 Schering Ag 1.4,7,10-Tetraazacyclododecan-Derivate, diese enthaltende pharmazeutische Mittel und Verfahren zu deren Herstellung
IT1274038B (it) * 1994-07-29 1997-07-14 Bracco Spa Chelanti macrociclici loro chelati e relativi usi in campo diagnostico
FR2725382B1 (fr) * 1994-10-05 1997-01-03 Commissariat Energie Atomique Polyazacycloalcanes, complexes tri-, tetra- ou pentaazamacrocycliques, procede de fabrication de ces polyazacycloalcanes substitues ou non et greffes sur un support et utilisations des polyazacycloalcanes
EP1322626B1 (fr) 2000-09-29 2008-11-05 Anormed Inc. Procede de preparation de polyamines cycliques a protection n-1 comportant n azotes sur leur noyau, et produits associes
US20040034223A1 (en) * 2002-02-07 2004-02-19 Covalent Partners, Llc. Amphiphilic molecular modules and constructs based thereon
EP1481268A4 (fr) * 2002-02-07 2005-06-29 Covalent Partners Llc Compositions pour nanofilms et membrane
US20040106741A1 (en) * 2002-09-17 2004-06-03 Kriesel Joshua W. Nanofilm compositions with polymeric components
KR101502180B1 (ko) 2006-08-30 2015-03-12 지이 헬스케어 에이에스 동적 핵 분극화 방법 및 이러한 방법에서 사용되는 화합물 및 조성물
FR2911340B1 (fr) * 2007-01-16 2009-04-17 Commissariat Energie Atomique Materiau comprenant des polyazacycloalcanes, greffes sur des fibres de polypropylene, son procede de preparation, et procede d'elimination de cations metalliques d'un liquide
WO2008134289A2 (fr) * 2007-04-26 2008-11-06 Mallinckrodt Inc. Complexes de lanthanide insaturés de manière coordonnée à relaxivité élevée
EP2457594A1 (fr) 2010-11-05 2012-05-30 Bracco Imaging S.p.A Système CEST démontrant une réactivité indépendante de la concentration
GB2489991B (en) 2011-04-15 2013-10-02 London Metropolitan University Europium and terbium complexes and their use

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3772785D1 (de) * 1986-01-23 1991-10-17 Squibb & Sons Inc 1-substituiertes-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecan und analoga.
US4885363A (en) * 1987-04-24 1989-12-05 E. R. Squibb & Sons, Inc. 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
US5271927A (en) * 1986-02-13 1993-12-21 Celltech Limited Antibody conjugates with macrocyclic ligands
US5064956A (en) * 1987-06-24 1991-11-12 The Dow Chemical Company Process for preparing mono-n-alkylated polyazamacrocycles
GB8719042D0 (en) * 1987-08-12 1987-09-16 Parker D Conjugate compounds
BR8907277A (pt) * 1988-12-22 1991-03-26 Dow Chemical Co Processo para preparar poliazamacrociclos mono-n-alquilados
FR2654102B1 (fr) * 1989-11-09 1992-01-10 Air Liquide Procede de synthese de derives polyazotes cycliques.
DE3938992A1 (de) * 1989-11-21 1991-05-23 Schering Ag Kaskadenpolymer-gebundene komplexbildner, deren komplexe und konjugate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel
US5236695A (en) * 1989-11-27 1993-08-17 Concat, Ltd. MRI image enhancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands
IT1243801B (it) * 1990-08-29 1994-06-28 Bracco Ind Chimica Spa Intermedi per agenti chelanti con simmetria prefissata, e procedimentoper la loro preparazione
JPH0797340A (ja) * 1993-06-03 1995-04-11 Terumo Corp Ｍｒｉ造影剤組成物

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US5705637A (en) 1998-01-06
US5677446A (en) 1997-10-14
NO974170D0 (no) 1997-09-09
WO1996028433A1 (fr) 1996-09-19
US5631368A (en) 1997-05-20
AU4839196A (en) 1996-10-02
NO974170L (no) 1997-11-07
CA2214990A1 (fr) 1996-09-19
GB9504910D0 (en) 1995-04-26
EP0815091A1 (fr) 1998-01-07

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